Neuroblastoma and Its Zebrafish Model.
Neuroblastoma and Its Zebrafish Model.
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神经母细胞瘤及其斑马鱼模型。
DOI：
10.1007/978-3-319-30654-4_20
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发表时间：
2016
影响因子：
--
通讯作者：
ThomasLook,A
中科院分区：
文献类型：
--
作者：
Zhu,Shizhen;ThomasLook,A
神经母细胞瘤是一种发生于周围交感神经系统(PSN)的重要发育性肿瘤，约占儿童癌症相关死亡的10 %。最近的基因组分析已经确定了这种肿瘤的一系列基因变化。在20 %的病例中发现MYCN癌基因的扩增，并经常伴随ALK(间变性淋巴瘤激酶)基因的突变激活，这表明它们在肿瘤的启动和扩散中具有协同作用。在癌症研究中，了解复杂的基因变化如何在肿瘤发生中共同发挥作用一直是一项持续而艰巨的任务。在神经母细胞瘤中，通过建立过表达人MYCN并激活PSN中的ALK的转基因斑马鱼模型，解决了这一挑战，导致了与人类神经母细胞瘤非常相似的肿瘤，并为探索这种肿瘤的发病机制提供了新的机会。例如，在这个模型中，激活的ALK和MYCN的共同表达使神经母细胞瘤的外显率增加了两倍，并显著加速了肿瘤的发生，证明了这些修饰基因在肿瘤发展中的相互作用。此外，MYCN过表达诱导肾上腺交感神经母细胞增殖，阻止嗜铬细胞分化，最终在增生性交感肾上腺细胞中触发发育时序的凋亡反应。在MYCN过表达的背景下，激活的ALK提供了阻止这种凋亡反应的生存信号，允许增生性神经母细胞的持续扩张和致癌转化，从而促进了向神经母细胞瘤的进展。斑马鱼模型的这种应用表明了它在合理评估定义神经母细胞瘤发病机制的多基因变化方面的价值，并为未来的研究指明了方向，以确定治疗干预的新靶点。
Neuroblastoma, an important developmental tumor arising in the peripheral sympathetic nervous system (PSNS), accounts for approximately 10 % of all cancer-related deaths in children. Recent genomic analyses have identified a spectrum of genetic alterations in this tumor. Amplification of theMYCNoncogene is found in 20 % of cases and is often accompanied by mutational activation of theALK(anaplastic lymphoma kinase) gene, suggesting their cooperation in tumor initiation and spread. Understanding how complex genetic changes function together in oncogenesis has been a continuing and daunting task in cancer research. This challenge was addressed in neuroblastoma by generating a transgenic zebrafish model that overexpresses humanMYCNand activatedALKin the PSNS, leading to tumors that closely resemble human neuroblastoma and new opportunities to probe the mechanisms that underlie the pathogenesis of this tumor. For example, coexpression of activatedALKwithMYCNin this model triples the penetrance of neuroblastoma and markedly accelerates tumor onset, demonstrating the interaction of these modified genes in tumor development. Further,MYCNoverexpression induces adrenal sympathetic neuroblast hyperplasia, blocks chromaffin cell differentiation, and ultimately triggers a developmentally-timed apoptotic response in the hyperplastic sympathoadrenal cells. In the context ofMYCNoverexpression,activated ALK provides prosurvival signals that block this apoptotic response, allowing continued expansion and oncogenic transformation of hyperplastic neuroblasts, thus promoting progression to neuroblastoma. This application of the zebrafish model illustrates its value in rational assessment of the multigenic changes that define neuroblastoma pathogenesis and points the way to future studies to identify novel targets for therapeutic intervention.